Millions of people around the world are diagnosed with cancer each year. The rapid proliferation of mutated cells can fatally risk health and well-being. Since President Richard Nixon declared the ‘war on cancer’ in 1971, billions of dollars have gone toward cancer research and how to better treat it. Various therapies have emerged to treat specific cancers based on their mutation and how the cancer progresses. However, the standard-of-care for most cancers in the clinic is chemotherapy. Although it can be toxic, it is the best treatment currently for many patients.
Chemotherapy is a form of treatment that uses chemicals to stop cancer cell proliferation and eliminate the tumor. Some chemotherapies are designed to starve cancer cells. Specifically, different drugs can stop nutrients from reaching the cancer cells and prevent them from proliferating and expanding. This form of therapy can be delivered orally, by injection, intravenously (IV), or topically. Unfortunately, chemotherapy can be toxic because it is not specific to cancer cells. These chemicals can also infiltrate healthy cells and cause off-target affects and make the patient feel ill. As a result, many patients are weakened by this therapy and need a measurable amount of time to recover. Additionally, some cancer cells become resist to chemotherapy and expand at the time of treatment or in the future. Scientists are currently working to understand more about the interaction between cancer cells and chemotherapy to develop more effective treatments.
A recent paper in Nature Metabolism, by Dr. Richard Possemato and others, demonstrate that glucose restriction (elicited by chemotherapy) in tumor cells protects them from cell death. Possemato is an Associate Professor in the Department of Pathology at the New York University Grossman School of Medicine. His work focuses on tumor metabolism and investigating the different metabolic pathways within cells that dictate their function.
Possemato and his team used three drugs they classify as glucose restrictive chemotherapies, including raltitrexed, N-(phosphonacetyl)-I-aspartate (PALA), and brequinar (BRQ). These three drugs prevent cancer cells from generating nucleotides for deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). As a result, tumor cells do not proliferate and usually self-destruct. However, researchers demonstrate that some cancer cells become resistant to nutrient starvation and survive. The team discovered that the inhibition of nucleotide generation stalls cancer cells and makes chemotherapy less effective. More specifically, cancer cells slow down their glucose consumption, which allows them to survive longer. Once glucose and other nutrients are completely gone, then the cells will self-destruct. The team also found that the low-glucose conditions prevented cell death proteins to activate, further preventing cell death and promoting tumor survival.
Low-glucose environments alter the metabolism of tumor cells to resist chemotherapy. This new advancement lays foundational groundwork to understand how to better develop therapeutic treatments. Researchers suspect combination therapies may resolve this issue and overcome chemotherapy resistance. This work can also apply to personalized medicine by determining how a patient’s tumor cells react in low-glucose environments to better predict an optimal treatment plan. Overall, this work provides knowledge that helps us understand the mechanism behind tumor resistance and has the potential to advance clinical care through enhanced therapeutic treatments.
Paper, Nature Metabolism, Richard Possemato, New York University Grossman School of Medicine